The prevalence of symptomatic osteoarthritis (OA) is higher in some joints, e.g. the knee, than in others, e.g. the ankle. The goal of this project is to compare normal articular cartilage and chondrocytes from these two joints of the same human donor obtained through the Regional Organ Bank of Illinois. Even though the structure/function relationship of these two joints may explain the different prevalence of OA in the knee and ankle, our preliminary data shows that there are significant biochemical differences between the two cartilages. The ankle chondrocytes are less responsive to catabolic mediators that may be due to decreased number of receptors. Compositional analyses show a higher collagen and proteoglycan content with lower water content; thus, the matrix components are more highly concentrated in the ankle cartilage. This is consistent with our biomechanical data showing that ankle chondrocytes form a matrix that is dynamically stiffer with lower hydraulic permeability. Ankle chondrocytes also had decreased gene expression of some matrix metalloproteinases. These data suggest that there are significant differences between normal knee and ankle cartilages that may make the ankle more resistant to degradation and provide protection that may make the ankle more resistant to degradation and provide protection from the progressive destructive changes in OA. Additional protection for the cartilage may be provided by a less responsive underlying bone since analyses of the subchondral bone in the ankles show no increase in bone density with severely damaged cartilage has been reported for the knee. Our hypothesis that the rarity of OA in the ankle joint may be due to the fact that its cartilage is more resistant than knee cartilage to progressive degeneration as a result of 1) decreased responsiveness to catabolic factors, 2) the initiation of repair following and/or 3) biochemical composition, gene expression and biomechanical properties of the cartilage as well as the underlying bone. Our proposed comparative studies not only between the cartilage derived from the different joints but also their degree of damage via biochemical, metabolic, biomechanical modifications will lead to a better understanding of the differences between the two joints. These data may ultimately be useful in the treatment of the OA patient by providing insight into those mechanisms involved in progressive degenerative changes leading to OA in one joint but not the other.